Rheumatic diseases are the most common chronic musculoskeletal diseases. These diseases are different individual illnesses with differential features, treatments, complications, and prognoses. They are similar in that they have a tendency to affect the joints, muscles, ligaments, cartilage and tendons, and many have the potential to affect internal body areas (The Merck Manual, 17th edition, 1999, Merck & Co., Inc).
While inflammation is one symptom of chronic musculoskeletal diseases, the pain and stiffness of the joints and muscles is particularly debilitating, as this physically inhibits movement and lessens the motivation for daily activities. Thus, these diseases may become a disabling conditions. Most of these diseases are chronic, progressive, and require long-term medication.
Arthritis is classified as one of the rheumatic diseases. It is a disorder featuring chronic inflammation of joints. There are over one hundred forms of arthritis, which range from those related to wear and tear of cartilage (such as osteoarthritis) to those associated with inflammation resulting from an over-active immune system (such as rheumatoid arthritis). Arthritis sufferers include men and women, children and adults. Approximately 350 million people worldwide have arthritis, and this figure increases by hundreds of thousands every year.
Causes of arthritis include injury (leading to osteoarthritis), abnormal metabolism (such as gout and pseudogout), inheritance, infections, as well as for unclear reasons (such as Rheumatoid arthritis and Systemic lupus erythematosus).
Symptoms of an established arthritis condition include pain and limited function of joints. Inflammation of the joints from arthritis is characterized by joint stiffness, swelling, redness, and warmth. Tenderness of the inflamed joint can be present, as well as fever, fatigue and even symptoms from abnormalities of organs such as the lungs, heart, or kidneys.
It has been estimated that the total cost of the arthritis bill for the United States, in terms of hospitalizations, doctor visits, medications, physical therapies, nursing home care, lost wages, early death, and family discord is over $50 billion dollars annually. The CDC's National Center for Chronic Disease Prevention and Health Promotion has concluded that the total costs attributable to arthritis and other rheumatic conditions (AORC) in the United States in 2003 was approximately $128 billion. This equaled 1.2% of the 2003 U.S. gross domestic product. National medical costs attributable to AORC grew by 24% between 1997 and 2003. This rise in medical costs resulted from an increase in the number of people with AORC (Yelin E., Murphy L., Cisternas M. G., Foreman A. J., Pasta D. J., Helmick C. G. Medical Care Expenditures and Earnings Losses of Persons with Arthritis and Other Rheumatic Conditions in 2003 with Comparisons to 1997. Arthritis Rheum. 2007, 56(5):1397-1407).
Rheumatoid arthritis and osteoarthritis are the two major forms of arthritis.
Rheumatoid arthritis (RA) is a chronic, systemic disease characterized by an inflammatory, erosive synovitis. Its pathological diagnosis is hyperplasia of synoviocytes, hyperaemia, thickening of blood vessel walls, infiltration of inflammatory cells, hyperplasia, transparency, and degeneration of fibrotic tissues. Changes in the synovium are marked by the formation of new blood vessels (termed angiogenesis), which play a key role in the formation and maintenance of a pannus of inflammatory vascular tissue. This pannus covers and erodes articular cartilage, eventually leading to joint destruction. The etiology of RA is unknown. Pathogens, environmental and genetics factors among others have been associated as responsible for triggering an uncontrolled immune reaction. According to theory of “mistaken identity”, an offending organism causes an immune response that leaves behind antibodies that are specific to that organism. However, the antibodies are not specific enough, and they will begin an immune attack against the synovium, because some molecule in the synovium “looks like” a molecule on the offending organism that created the initial immune reaction. Thus, rheumatoid arthritis is considered an autoimmune disorder associated with a pathological angiogenesis of affected tissues. (William P A. The pathophysiology and treatment of rheumatoid arthritis. Arthritis Rheumatism 1997, 40(4): 585-597; Paleolog E. M. Angiogenesis in rheumatoid arthritis. Arthritis Res. 2002, 4(3):S81-S90).
The symptoms that distinguish rheumatoid arthritis from other forms of arthritis are inflammation and soft-tissue swelling of many joints at the same time (polyarthritis). Typically, the joints are initially affected asymmetrically, and then in a symmetrical fashion as the disease progresses. The pain generally improves with use of the affected joints, and usually, there is stiffness of all joints in the morning that lasts over one hour. Thus, the pain of rheumatoid arthritis is usually worse in the morning compared to the classic pain of osteoarthritis, where the pain worsens over the day as the joints are used. Extra-articular manifestations also distinguish this disease from osteoarthritis. For example, most patients also suffer with anemia, either as a consequence of the disease itself or as a consequence of gastrointestinal bleeding as a side effect of drugs used in treatment, especially NSAIDs (non-steroidal anti-inflammatory drugs) used for analgesia.
Rheumatoid arthritis is a disabling and painful inflammatory condition, which can lead to substantial loss of mobility due to pain and joint destruction. RA is a systemic disease, often affecting extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs, and muscles. The course of the disease varies greatly from patient to patient. Some patients have mild short-term symptoms, but in most, the disease is progressive for life. About 60% of RA patients will be unable to work 10 years after the onset of the disease and their quality of life will be severely reduced (Tammi L. Shlotzhauer, M. D., James L. McGuire, M. D. Living with Rheumatoid Arthritis. Johns Hopkins University. 2nd ed. 2003, 312 pp).
Rheumatoid arthritis is one of the top five common human diseases. World Health Organization estimated that RA affects 1% of the human population on earth. Approximately 2.1 million Americans suffer from rheumatoid arthritis. The incidence of RA is in the region of 3 cases per 10,000 population per annum. Onset is uncommon under the age of 15 and from then on the incidence increases with age until the age of 80. The prevalence rate is 1%, with women affected three to five times as often as men. It is 4 times more common in smokers than non-smokers. There are also racial differences: some Native American groups have higher prevalence rates (5-6%), while black persons from the Caribbean region have lower prevalence rates.
Osteoarthritis (OA) is a chronic disease of the joints, especially the weight-bearing joints, that develops when the lining of joints degenerates, leading to lipping and spurring of bones, pain, and decreased mobility and function. Osteoarthritis, is also known as hypertrophic arthritis, degenerative arthritis, degenerative joint disease, proliferative arthritis or osteoarthrosis (The Merck Manual, 17th edition, 1999, Merck & Co., Inc).
The cause of osteoarthritis is not entirely clear, however, it may be a combined result of mechanical impairment and physiological alterations with aging, as well as other factors such as obesity, bone density, injury and genetics. The onset of OA is gradual and most often affects the hips, knees, fingers, and spine, although other joints may be involved. Pain is the main symptom, which usually worsens with exercise and is relieved by rest. Morning stiffness is also common and diminishes with movement. As OA progresses, joint motion is lost, and tenderness and grating sensations may develop. OA of the spine may lead to shooting pains down the arms or legs (Kenneth D. Brandt M D. 2005. Diagnosis and Nonsurgical Management of Osteoarthritis, ed: Professional Communications Incorporated, Caddo Okla., 384 pages).
Osteoarthritis is classified as non-inflammatory arthritis. However, recent research shows that although there is usually no appreciable swelling in the early stage of the disease, as the arthritis progresses the inflammation process takes place (Roach H. I., Aigner T., Soder S., Haag J., Welkerling H. Pathobiology of osteoarthritis: pathomechanisms and potential therapeutic targets. Curr Drug Targets. 2007, 8(2):271-282.). In osteoarthritis, the top layer of cartilage breaks down and wears away. This allows bones under the cartilage to rub together. The rubbing causes pain, swelling, and loss of motion of the joint. Over time, the joint may lose its normal shape. Also, bone spurs may grow on the edges of the joint. Bits of bone or cartilage can break off and float inside the joint space, causing more pain and damage.
Damage due to OA progresses over time and may result in several problems. The person may have pain, especially when moving a joint. Sometimes, a grating sound can be heard when the roughened cartilage on the surfaces of the bones rub together. Bumps or swelling may appear, especially on the fingers and feet. A joint may feel sore and stiff, and the joint will not move as easily or as far as it once did. All these changes can make it hard to move around and to do everyday tasks. People with osteoarthritis often have joint pain and reduced motion. Advanced OA is a disabling condition.
OA is the most common type of arthritis, especially among elders; 50% of people over age 50 and 80% of people over age 55 have some clinical symptoms of this disease. People that are over 65 generally suffer from OA. More than 21 million Americans have osteoarthritis.
Generally speaking, the process of clinically detectable osteoarthritis is irreversible, and typical treatment consists of medication or other interventions that can reduce the pain of OA, and thereby improve the function of the joint. Therapies that manage osteoarthritis pain and improve function include exercise, weight control, rest, pain relief, alternative therapies and surgery (The Merck Manual, 17th edition, 1999, Merck & Co., Inc).
For rheumatoid arthritis, the basic goal of treatment is to reduce pain and inflammation; to prevent deformation of bone, cartilage, and soft tissues; and to maintain the normal function of the joints; thereby maintaining the normal daily activities of the patients for the longest possible period.
Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics (O'Dell J. Therapeutic strategies for rheumatoid arthritis. N Engl J Med, 2004, 350(25): 2591-2602). DMARDs have been found to produce durable remissions and delay or halt disease progression through their cytotoxic and/or immunosuppressive properties. In particular, they prevent bone and joint damage from occurring secondary to the uncontrolled inflammation (Vital E., Emery P. Advances in the treatment of early rheumatoid arthritis. Am Fam Physician. 2005, 72 (6): 1002-1004). This is important, as such damage is usually irreversible. Anti-inflammatories and analgesics improve pain and stiffness but do not prevent joint damage or slow the disease progression.
DMARDs can be subdivided into traditional small molecular mass drugs synthesized chemically (azathioprine, cyclosporine A, D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate (MTX), minocycline and sulfasalazine (SSZ)), and newer biological agents with immuno-modulatory properties, produced through genetic engineering such as: tumor necrosis factor alpha (TNFa) blockers (etanercept, infliximab, adalimumab), interleukin-1 blockers (anakinra), anti-B cell (CD20) antibody (rituximab), blockers of T cell activation (abatacept), etc. (Hasler P. Biological therapies directed against cells in autoimmune disease. Springer Semin Immunopathol. 2006, 27 (4): 443-456; Dombrecht E. J., Aerts N. E., Schuerwegh A. J., Hagendorens M. M., Ebo D. G., Van Offel J. F., Bridts C. H., Stevens W. J., De Clerck L. S. Influence of anti-tumor necrosis factor therapy (Adalimumab) on regulatory T cells and dendritic cells in rheumatoid arthritis. Clin Exp Rheumatol. 2006, 24(1):31-37). It has also been proposed that systemically using interleukin-4 (IL-4), it is possible to arrest the clinical progression of collagen-induced arthritis (CIA), a mouse model for human rheumatoid arthritis, and effectively protect against cartilage and bone destruction (Joosten L. A., Lubberts E., Helsen M. M., Saxne T., Coenen-de Roo C. J., Heineg{dot over (a)}rd D., van den Berg W. B. Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis. Arthritis Res. 1999, 1(1):81-91; U.S. Pat. No. 5,955,315; U.S. Pat. No. 5,951,973). IL-4 stimulates proliferation, differentiation and activation of several cell types, including fibroblasts, endothelial cells and epithelial cells. IL-4 is also known to be a potent anti-inflammatory cytokine that acts by inhibiting the synthesis of pro-inflammatory cytokines such as IL-1, TNF-alpha, IL-6, IL-8 and IL-12 by macrophages and monocytes. Moreover, IL-4 stimulates the synthesis of several cytokine inhibitors such as interleukin-1 receptor antagonist (IL-1Ra), soluble IL-1-receptor type II, and TNF receptors. IL-4 suppresses metalloproteinase production and stimulates tissue inhibitors of metalloproteinase-1 production in human mononuclear phagocytes and cartilage explants, indicating a protective effect of IL-4 towards extracellular matrix degradation. Furthermore, IL-4 inhibits both osteoclast activity and survival, and thereby blocks bone resorption in vitro.
Although DMARDs can be effective to improve prognosis of RA, this class of drugs has many serious side effects, and often, they are not tolerated by patients. The most important and most common adverse events relate to liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline), ocular toxicity (hydroxychloroquine) and infections (azathioprine, cyclosporine A).
More recently, there have been emerging new therapies based on CD25+ T regulatory cells (Treg cells). Treg cells are a naturally occurring suppressor T-cell population that regulates a wide variety of immune responses. A major function of CD25+ Treg cells is to inhibit the activity of self-reactive T cells that can potentially cause autoimmune disease (Zwar T. D., van Driel I. R., Gleeson P. A. Guarding the immune system: suppression of autoimmunity by CD4+ CD25+ immunoregulatory T cells. Immunol Cell Biol. 2006, 84(6):487-501; Suri-Payer E, Fritzsching B. Regulatory T cells in experimental autoimmune disease. Springer Semin Immunopathol. 2006, 28(1):3-16). It has been shown in different experimental models that Treg-cell-based therapies could improve clinical and laboratory variables in CIA, being a very promising therapeutic approach to target the pathogenic mechanism of autoimmune arthritis (Gonzalez-Rey E, Femandez-Martin A, Chorny A, Delgado M. Vasoactive intestinal peptide induces CD4+, CD25+T regulatory cells with therapeutic effect in collagen-induced arthritis. Arthritis Rheum. 2006, 54(3):864-876; Toh M. L., Miossec P. The role of T cells in rheumatoid arthritis: new subsets and new targets. Curr Opin Rheumatol. 2007, 19(3):284-288). Other cell therapies under development for treating rheumatic diseases are: T-cell vaccination (Chen G., Li N., Zang Y. C., Zhang D., He D., Feng G., Ni L., Xu R., Wang L., Shen B., Zhang J. Z. Vaccination with selected synovial T cells in rheumatoid arthritis. Arthritis Rheum. 2007, 56(2):453-463), and therapy using mesenchymal stem cells (Augello A, Tasso R, Negrini S M, Cancedda R, Pennesi G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 2007, 56(4):1175-1186).
Anti-inflammatory agents for treatment of RA or OA include: non-steroidal anti-inflammatory drugs (NSAIDs, most also act as analgesics) and glucocorticoids.
NSAIDs are the major anti-arthritis drugs. They reduce inflammation and pain in the early stage of the disease by inhibiting cyclooxygenase (COX), and therefore the production of prostaglandins (PG), which play a central role in inflammation and pain (Green G A. Understanding NSAIDS: from aspirin to COX-2. Clin Cornerstone. 2001, 3:50-59). The NSAIDs are effective in treating the symptoms of the acute arthritis, but have little effect on preventing the progression of the disease. High doses are often required. Currently, there are many kinds of drug like this, namely acemetacin, diclofenac, ibuprofen, indomethacin, meloxicam, ketoprofen, sulindac, auranofin, naproxen, nabumetone, piroxicam, mecolfenamic acid, chlofenamic acid, mefenamic acid, pirprofen, fenbufen, tolmetin, flufenamide acid, fenoprofen, methocarbamol and nimesulide. NSAIDs are the first-line anti-arthritis drugs and are critical in treating arthritis, however, their effectiveness in treating arthritis remains controversial among the doctors and patients. Moreover, their severe adverse effects cannot be overlooked because the drugs listed above inhibit the production of COX-1 and COX-2 simultaneously and the usage often brings about many severe adverse effects such as gastrointestinal complex syndrome, upset stomach, abdominal pain, ulcers, gastrointestinal bleeding, as well as damage to the kidneys, liver, and blood system. Severe adverse side effects have been reported in one third to nearly one half of chronic NSAID users; and reports estimate 100,000 NSAID-related hospitalizations and up to 20,000 related death in United States annually (Fries J. Toward an understanding of NSAID-related adverse events: the contribution of longitudinal data. Scand. J. Rheumatol. 1996, 102(suppl):3-8; Miller J. L. Decisions loom on selective COX-2 inhibitors. Am J. Health Sys Pharm. 1999, 56:106-107).
Another type of NSAIDs, COX-2 selective inhibitors (such as celecoxib, and the withdrawn rofecoxib and valdecoxib) reduce the risk of gastrointestinal bleeding or peptic ulceration. However, these latter NSAIDs carry an elevated risk for cardiovascular disease, and some have now been withdrawn from the market. More recently, the use of dual 5-LOX/COX inhibitors (such as licofelone, tepoxalin) have been proposed as potential new drugs to treat inflammation (Martel-Pelletier J, Lajeunesse D, Reboul P, Pelletier J-P. Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis 2003, 62:501-509). They act by blocking the formation of both prostaglandins and leukotrienes, but do not affect lipoxin formation. Such combined inhibition avoids some of the disadvantages of selective COX-2 inhibitors and spares the gastrointestinal mucosa. Nonetheless, it is foreseen that these kinds of NSAIDs will continue to have a deleterious effects on kidneys, liver and blood system.
Corticosteroids are effective immunosuppresors, and the most effective anti-inflammatory drugs as a short-term medication, but they cannot cure arthritis. Their side effects increase as the dose and the length of the treatment increase. It is therefore important to weigh their efficacy, carefully against their side effects. The corticosteroids are mainly glucocorticoids such as cortisone and prednisolone. The glucocorticoids, although effective in reducing inflammation, can cause infection, osteoporosis, and dysfunction of the adrenal cortex. Therefore, it is recommended that glucocorticoids are not used as a long-term medication. Most doctors nowadays loath using steroids in the treatment of arthritis as their effect is modest and their adverse effects may outweigh their benefits (Barnes P. J. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond). 1998, 94(6):557-572).
Analgesics are commonly used to treat the pain from arthritis. They include: acetaminophen (paracetamol), opiates, diproqualone and topical lidocaine. Acetaminophen is commonly used to treat the pain from arthritis, although unlike NSAIDs, acetaminophen does not treat the inflammation. This is because it inhibits COX at central level, but not in peripheral tissues. Opioids (hydrocodone, oxycodone or morphine) may be necessary, but these should be reserved for very severe cases, and are rarely medically necessary for chronic pain.
It is believed that lifestyle plays an important role in the occurrence and development of many musculoskeletal diseases, including arthritis, and a lifestyle change may be needed for effective symptomatic relief (De Filippis L., Gulli S., Caliri A., Romano C., Munaoò F., Trimarchi G., La Torre D., Fichera C., Pappalardo A., Triolo G., Gallo M., Valentini G., Bagnato G. Epidemiology and risk factors in osteoarthritis: literature review data from “OASIS” study. Reumatismo. 2004, 56(3):169-184). Physical and emotional stress, improper diet, obesity and smoking could play a significative role in aggravating these diseases (Voigt L. F., Koepsell T. D., Nelson J. L., Dugowson C. E., Daling J. R. Smoking, obesity, alcohol consumption, and the risk of rheumatoid arthritis. Epidemiology. 1994, 5(5):525-532). On the other hand, conservative measures, such as healthy diet, weight control, appropriate rest and exercise are usually beneficial to sufferers. Nutritional changes shown to aid in the treatment of OA include decreasing saturated fat intake and using a low energy diet to reduce body fat (Wilhelmi G., Potential effects of nutrition including additives on healthy and arthrotic joints. 1. Basic dietary constituents. Zeitschrift fur Rheumatologic. 1993, 52(3):174-179; Christcnsen R., Astrup A., Bliddal H. Weight loss: the treatment of choice for knee osteoarthritis? A randomized trial. Osteoarthritis Cartilage. 2005, 13(1):20-27). Reducing sugar, processed foods, fatty foods and nightshade vegetables have helped many. Some doctors believe that a low fat vegetarian diet can reduce arthritis symptoms. A macrobiotic diet has been known to reduce symptoms as well. Nicotinamide (niacinamide), a derivative of vitamin B-3 which is typically used for nutritional supplementation, can be used for the treatment of arthritis. One controlled pilot study showed that subjects with OA who received nicotinamide (3 g per day) reduced their non-steroidal anti-inflammatory (NSAID) medication and increased joint mobility significantly when compared with placebo controls (Jonas W. B., Rapoza C. P., Blair W. F. The effect of niacinamide on osteoarthritis: a pilot study. Inflamm Res. 1996, 45(7):330-334). It has been shown that at high doses, nicotinamide is a potent modulator of several proinflammatory cytokines by a mechanism still not well understood (Ungerstedt J. S., Blömback M., Söderström T. Nicotinamide is a potent inhibitor of proinflammatory cytokines. Clin Exp Immunol. 2003, 131(1):48-52). Unlike OA, there is no diet that has been shown to alleviate rheumatoid arthritis, although it has been demonstrated in RA patients that high intake (more than 3 g EPA+DHA daily) of omega-3 fatty acids from fish oil has anti-inflammatory effects (van der Tempel H., Tulleken J. E., Limburg P. C., Muskier F. A. J., van Rijswijk. Effects of fish oil supplementation in rheumatoid arthritis. Ann. Rheum. Dis. 1990, 49(2):76-80).
The human body can produce all but two of the polyunsaturated fatty acids (PUFAs) it needs. These two, omega-6 linoleic acid (LA, 18:2ω6) and omega-3 alpha-linolenic acid (LNA, 18:3ω3), are widely distributed in plant oils. In addition, fish oils contain the longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA, 20:5ω3) and docosahexaenoic acid (DHA, 22:6ω3). Scientists discovered the many benefits of EPA and DHA in the early 1970's, when Danish physicians observed that Greenland Eskimos had an exceptionally low incidence of heart disease and arthritis despite the fact that they consumed a high-fat diet (Bang H O, Dyerberg J, Nielsen A B: Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet 1971, 1:1143-1145). The essential fatty acids are important in several human body systems, including immune, blood and nervous systems. High intake of oils rich in omega-3 PUFAs (n-3 PUFAs) is believed to result in a decrease in cell membrane arachidonic acid (AA) levels and a concomitant decrease in the synthesis of pro-inflammatory eicosanoids (series-2 prostaglandins, thromboxanes and series-4 leukotrienes) from AA, while substantially increasing the substrate for anti-inflammatory compounds, such as prostaglandin E3 Moreover, the decrease in the production of leukotrienes can inhibit neutrophil function and their cytotoxic activity (Simopoulos A. P. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002, 21(6):495-505; U.S. Pat. No. 6,485,752). The consumption of animal fats and omega-6 vegetable oils increases the AA content of cell membranes, and for this reason, the anti-inflammatory diet to treat arthritis is based on the reduction of dietary sources of AA, while increasing the intake of omega-3 PUFAs from cold-water fish and/or good quality flax seed oils. Research on inflammatory conditions report effective oral doses ranging from 1.2 to 4.6 g/day of fish oil (600 to 2300 mg/day EPA+DHA) (Wallace J. M. Nutritional and Botanical Modulation of the inflammatory cascade—eicosanoids, cyclooxygenases, and lipoxygenases—as an adjunct in cancer therapy. Int Cancer Therapies. 2002, 1(1):7-37).
Regular exercise, if possible, starting with home joint protection exercises (JPE) followed by walking or swimming, is encouraged. Regular exercise is important for maintaining joint mobility and making the joint muscles stronger (Stamm T. A., Machold K. P., Smolen J. S., Fischer S., Redlich K., Graninger W., Ebner W., Erlacher L. Joint protection and home hand exercises improve hand function in patients with hand osteoarthritis: a randomized controlled trial. Arthritis Rheum. 2002, 47 (1): 44-49). Some researches suggest that moderate alcohol consumption lowers the risk of developing arthritis (Turesson C. Increased Alcohol Intake Associated with Decreased Risk of Developing Rheumatoid Arthritis. (Abstract) Paper presented at the annual European Congress of Rheumatology. Barcelona, Spain. Jun. 13-16, 2007. European League Against Rheumatism, Jun. 15, 2007; Myllykangas-Lusojarvi, R., Aho, K., Kautiainen, H., Hakala, M. Reduced incidence of alcohol related deaths in subjects with rheumatoid arthritis. Annals of Rheumatoid Diseases, 2000, 59, 75-76). It is also known that antioxidants, including vitamins C and E in both foods and supplements, provide pain relief from OA (McAlindon T. E., Jacques P., Zhang Y., Hannan M. T., Aliabadi P., Weissman B., Rush D., Levy D., Felson D. T. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum 1996; 39:648-656). It has also been found in one study, that an increase in vitamin K intake reduces the prevalence of arthroses (Neogi T., Booth S. L., Zhang Y. Q., Jacques P. F., Terkeltaub R., Aliabadi P., Felson D. T. Low Vitamin K Status is Associated with Osteoarthritis in the Hand and Knee. Arthritis Rheum. Abril, 2006; 54(4): 1255-1261), however, a robust explanation for this finding has not been advanced. Ginger rhizome (Zingiber officinale) extract has been used to improve knee symptoms in OA. Ginger, is supposed, can help reduce inflammation, as it relaxes the muscles surrounding blood vessels and facilitates blood flow throughout the body (Altman R. D., Marcussen K. C. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum. 2001, 44(11):2531-2538). Treatments also include rest, relaxation and psychotherapy, as dealing with chronic pain can be difficult and often results in depression.
Although there are many anti-arthritis drugs in the markets, there is no very effective drug to cure or to control the progression of arthritis, especially for rheumatoid arthritis and osteoarthritis. Many of the NSAIDs have serious gastrointestinal and circulatory side effects. The DMARDs also have serious toxic effects on the liver and kidneys. The glucocorticoids, do not cure these diseases and have strong noxious effects as long-term medications. Other anti-arthritis drugs also have unclear efficiency problems, including slow action and severe side effects. In summary, there is a need for effective and side effect-free medications for arthritis and other musculoskeletal diseases that base their action on the possible causes of these diseases, and not on the symptoms or collateral disorders.
Contrary to what it is believed overall, we consider that the primary cause of arthritis and other musculoskeletal and connective tissues diseases of unknown origin is a chronic deficient blood flow to involved tissues. We have arrived at this conclusion considering that many symptoms associated with deficient blood circulation like cramps, numbness, tingling, chills, and stiffness are already present at different levels and under different circumstances among patients, long before they show the typical acute clinical manifestations of these diseases. Moreover, factors deleterious to the blood system such as smoking, obesity, sedentariness, diabetes, unbalanced nutrition, stress, depression and aging, are conditions related to increasing risk of developing or aggravating arthritis and other musculoskeletal and connective tissue diseases. On the other hand, agents that promote angiogenesis and improve the blood circulation such as exercising, application of heat, moderate consumption of alcohol, nicotinamide, copper, ginger extract, and omega-3 fatty acids have been consistently reported as effective in treating and alleviating symptoms of these diseases.
Among other factors, we consider that atherosclerosis, calcification of capillary blood vessels, and sustained vasoconstriction due to high triglycerides and/or cholesterol levels, low absorption of vitamin K, stress and depression could lead to a microvascular rarefaction, improper vascular flow and a micro-localized low-level ischemia. These conditions will induce angiogenesis in affected tissues, but this healing process will not be properly accomplished due to the same factors that promoted it. The final result of this cascade of facts is the apoptosis of damaged cells. The genetic background and the sort of affected tissues will further determine the course of the disease (as for example the form of arthritis) with regard to the intensity of the inflammation and immune responses triggered by stressed or damaged cells. Of course, under these circumstances, also possible is the development of an altered angiogenesis. It is clear that among the genetic background and physiological factors, other processes detrimental to blood circulation, such as a chronic inflammation related to injuries or infections, could trigger the development of chronic musculoskeletal and connective tissues disorders.
It is noteworthy that very recently, Dr. David L. Katz and his colleagues, analyzing the symptoms of fibromyalgia syndrome (FMS), another musculoskeletal disease of unknown etiology and pathogenesis, advanced the hypothesis that the cause of this syndrome could be a vasomotor dysregulation in muscles leading to low-level ischemia and its metabolic sequelae; and encouraged the scientific community to test their idea (Katz D. L., Greene L., Ali A., Faridi Z. The pain of fibromyalgia syndrome is due to muscle hypoperfusion induced by regional vasomotor dysregulation. Medical Hypotheses. 2007, 69(3):517-525). On the other hand, the treatment proposed for FMS is based mainly on intravenous micronutrient therapy (IVMT), administering arginine (precursor of NO production (vasodilator) and promoter of growth hormone production), vitamins (B3, B6, C), malic acid, zinc, bioflavonoids, and other nutraceuticals; and is not directed to promote the angiogenesis and blood circulation in the affected tissues as a way to definitively cure the disease (on the contrary, some of these compounds are known inhibitors of angiogenesis). It is very interesting to the present invention that one of the most controversial therapies to treat FMS (St. Amand's protocol) is based on the phosphate accumulation theory, and requires limiting the exposure of patients to salicylic acid, and to use guaifenesin to remove the excess of phosphate from the body (Kathy Longley (2004). Are phosphates the hidden enemy? (PDF). Fibromyalgia Association UK. (http://ukfmsguai.tripod.com)). However, it is well known that salicylates are potent inhibitors of prostaglandins (stimulators of angiogenesis), and guaifenesin has skeletal muscle relaxant properties, and it may also inhibit platelet aggregation (it is a possible vasodilator and blood thinner).
Good blood flow is essential to supply oxygen, nutrients and other vital factors to cells and tissues in order to maintain their survival, normal functioning and regeneration capacity. When blood circulation is impaired, or when a wound occurs, affected cells will produce and release factors that promote angiogenesis as a way to restore normal physiological conditions. Angiogenesis is the formation of new capillary, blood vessels from an existent vascular bed. Angiogenesis is a complex and tightly regulated process, where a perfect balance between factors that stimulate and inhibits this process is crucial. Physiologically, the body controls angiogenesis through a series of “on” (endogenous stimulators) and “off” (endogenous inhibitors) regulatory switches. Some endogenous stimulators and inhibitors of angiogenesis are listed in Table 1. Up-regulated angiogenesis is believed to be a causal factor in certain pathological conditions such as cancer, diabetic retinopathy, arthritis (which we refute here), psoriasis, etc.; while, down-regulated angiogenesis is found to cause coronary artery disease or impaired healing of chronic ulcers (Folkman J., Shing Y. Angiogenesis. J. Biol. Chem. 1992, 267:10931-10934; Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other diseases. Net. Med. 1995, 1:27-31).
TABLE 1Some stimulators and inhibitors of Angiogenesis.StimulatorsInhibitorsAngiogeninTissue inhibitor ofmetalloprotease (TIMP-1,TIMP-2 and TMP-3)AngiotropinPlasminogen activatorinhibitor-1 (PAI-1)Epidermal growth factorInterleukin-10Fibroblast growth factor (acidic and basic)Interleukin-12Granulocyte-macrophage colony-Interferon-alphastimulating factorHepatocyte growth factorAngiopoietin-2Scatter factorAngiotensinPlacental growth factorAngiotensin-II (AT2 receptor)Platelet-derived growth factor-BBCaveolins 1 and 2Tumor necrosis factor-alphaEndostatinTransforming growth factor-betaProlactin (16 Kd fragment)Vascular endothelial growth factorPlatelet factor-4CathepsinThrombospondinGelatinase A, BTroponin-1StromelysinIsoflavonesUrokinase-type plasminogen activatorZincThymidine phosphorylaseFarnesyl transferaseGeranylgeranyl transferaseInterleukin-1Interleukin-6Interleukin-8Alpha/Beta 3 integrinAngiopoietin-1Angiostatin II (ATI receptor)Endothelin (ETB receptor)Erythropoietin (EPO)Nitric oxide synthaseNitric oxidePlatelet-activating factorAdiponectinThrombopoietinProstaglandins E1 and E2CopperAdenosineNicotinamide1-Butyryl glycerolHypoxia
The blockage of angiogenic stimulators and the use of angiogenesis inhibitors have been proposed as a therapeutic means to treat vascular proliferative disorders (Tai-Ping D. F. Rhys J., Roy B. Controlling the vasculature: angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. TiPS 1995, 16:57-66; Pandya N. M., Dhalla N. S., Santani D. D. Angiogenesis-a new target for future therapy. Vascular Pharmacology. 2006, 44:265-274). On the other hand, it has been shown in animal models that systemic or topical application of angiogenic stimulators such as basic Fibroblast Growth Factor (bFGF), Vascular Endothelial Growth Factor (VEGF), or Transforming Growth Factor (TGF) may accelerate and improve the healing of duodenal ulcers (Folkman J., Szabo S., Stovroff M., McNeil P., Li W., Shing Y. Duodenal ulcer. Discovery of a new mechanism and development of angiogenic therapy that accelerates healing. Ann Surg. 1991, 214(4):414-427), reverse diabetic or other kinds of wound healing impairments (Phillips L. G., Abdullah K. M., Geldner P. D., Dobbins S., Ko F., Linares H. A., Broemeling L. D., Robson M. C. Application of basic fibroblast growth factor may reverse diabetic wound healing impairment. Ann Plast Surg. 1993, 31(4):331-334; Beck L. S., DeGuzman L., Lee W. P., Xu Y., Siegel M. W., Amento E. P. One systemic administration of transforming growth factor-beta 1 reverses age- or glucocorticoid-impaired wound healing. J Clin Invest. 1993, 92(6):2841-2849), or produce therapeutic benefit in cases of severe limb ischaemia, myocardial, or cerebral infarcts (Roberts A. B., Sporn M. B., Lefer A. M. Cardioprotective action of transforming growth factor-beta. Trends Cardiovasc. Med. 1993, 3:77-81; Banai S., Jaklish M. T., Shou M. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factors in dogs. Circulation. 1994, 89:2183-2189; Takeshita S., Zheng L. P., Brogi E., Kearney M., Pu L. Q., Bunting S., Ferrara N., Symes J. F., Isner J. M. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest. 1994, 93(2):662-670). It has also been shown in an animal model that it is possible to induce angiogenesis through cell-therapy (Chen J., Zhang Z. G., Li Y., Wang L., Xu Y. X., Gautam S. C., Lu M., Zhu Z., Chopp M. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 2003, 92(6):692-699). However, therapeutic angiogenesis is not free from potential harmful effects. Animal studies and clinical trials suggested hypotension is associated with both bFGF and especially VEGF administration due to nitric oxide release and arteriolar vasodilatation (Ware J. A., Simons M. Angiogenesis in ischemic heart disease. Nat. Med. 1997, 3:158-164). Other concerns associated with angiogenic growth factors include plaque angiogenesis, proliferative retinopathy and occult malignancies (Simons M., Bonnow R. O., Chronos N. A. Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary. Circulation. 2000, 102:e73-e86). For these reasons, it is suggested that potent angiogenic growth factors should be used locally at high drug target level or low systemic exposure.